Dynamics of thyroid diseases and thyroid-axis gland masses.

Thyroid disorders are common and often require lifelong hormone replacement. Treating thyroid disorders involves a fascinating and troublesome delay, in which it takes many weeks for serum thyroid-stimulating hormone (TSH) concentration to normalize after thyroid hormones return to normal. This delay challenges attempts to stabilize thyroid hormones in millions of patients. Despite its importance, the physiological mechanism for the delay is unclear. Here, we present data on hormone delays from Israeli medical records spanning 46 million life-years and develop a mathematical model for dynamic compensation in the thyroid axis, which explains the delays. The delays are due to a feedback mechanism in which peripheral thyroid hormones and TSH control the growth of the thyroid and pituitary glands; enlarged or atrophied glands take many weeks to recover upon treatment due to the slow turnover of the tissues. The model explains why thyroid disorders such as Hashimoto's thyroiditis and Graves' disease have both subclinical and clinical states and explains the complex inverse relation between TSH and thyroid hormones. The present model may guide approaches to dynamically adjust the treatment of thyroid disorders.

An opponent process for alcohol addiction based on changes in endocrine gland mass.

Consuming addictive drugs is often initially pleasurable, but escalating drug intake eventually recruits physiological anti-reward systems called opponent processes that cause tolerance and withdrawal symptoms. Opponent processes are fundamental for the addiction process, but their physiological basis is not fully characterized. Here, we propose an opponent processes mechanism centered on the endocrine stress response, the hypothalamic-pituitary-adrenal (HPA) axis. We focus on alcohol addiction, where the HPA axis is activated and secretes ß-endorphin, causing euphoria and analgesia. Using a mathematical model, we show that slow changes in the functional mass of HPA glands act as an opponent process for ß-endorphin secretion. The model explains hormone dynamics in alcohol addiction and experiments on alcohol preference in rodents. The opponent process is based on fold-change detection (FCD) where ß-endorphin responses are relative rather than absolute; FCD confers vulnerability to addiction but has adaptive roles for learning. Our model suggests gland mass changes as potential targets for intervention in addiction.

Hormone seasonality in medical records suggests circannual endocrine circuits.

Hormones control the major biological functions of stress response, growth, metabolism, and reproduction. In animals, these hormones show pronounced seasonality, with different set-points for different seasons. In humans, the seasonality of these hormones remains unclear, due to a lack of datasets large enough to discern common patterns and cover all hormones. Here, we analyze an Israeli health record on 46 million person-years, including millions of hormone blood tests. We find clear seasonal patterns: The effector hormones peak in winter-spring, whereas most of their upstream regulating pituitary hormones peak only months later, in summer. This delay of months is unexpected because known delays in the hormone circuits last hours. We explain the precise delays and amplitudes by proposing and testing a mechanism for the circannual clock: The gland masses grow with a timescale of months due to trophic effects of the hormones, generating a feedback circuit with a natural frequency of about a year that can entrain to the seasons. Thus, humans may show coordinated seasonal set-points with a winter-spring peak in the growth, stress, metabolism, and reproduction axes.

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks.

Stress activates a complex network of hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders.

Early, rapidly progressive enteral nutrition promotes growth of very low birth weight (VLBW) infants.

AIM: This study describes the effects of a quality improvement program to promote improved postnatal nutrition on the growth of very low birth weight (VLBW) infants. METHODS: Daily data regarding nutrition and growth were collected from the medical record of VLBW infants born during 1995-2010. The infants were grouped by year of birth in order to compare infants from before, during and after the policy change. Evaluation of growth included age in days at a return to birth weight and the proportion of infants with weight below the 10th percentile at discharge. RESULTS: The caloric and protein intake improved significantly. The age at a return to birth weight fell (p < 0.01) from 14.6 ± 5 d to 11 ± 8 d after the change. The proportion of infants with a discharge weight below the 10th percentile for corrected age fell (p < 0.01) from 72.1% to 42.1%. Data on enteral feeding showed that increased rate of enteral feeds (EF) was associated with better growth (p < 0.001). CONCLUSION: Increasing awareness led to increase in caloric and protein intake in VLBW infants. Aggressive EF was associated with more rapid weight gain. However, the provision of protein and calories during the first 2 weeks of life still falls short of the latest European Society of Pediatric Gastroenterology, Hepatology and Nutrition recommendations.